Viral proliferation requires the interaction of viral regulatory proteins with their cognate recognition sequences within the viral genome. We wish to identify small molecules that will interfere with these DNA:protein interactions by binding in a sequence-specific manner tot he DNA recognition site. Toward this goal we will develop a binding inhibition assay that will be used to screen large libraries of biological and synthetic chemicals for the ability to disrupt specific DNA:protein complexes. In Phase I, the feasibility of assay development will be tested; in Phase II, the primary screening assay will be developed; in Phase III, corporate interactions with companies possessing libraries will be established and the libraries will be screened. The specific goals of Phase I are to 1) design a model assay system for development in Phase II; 2) demonstrate feasibility by showing that the binding of a competing molecule blocks the binding of a regulatory protein. Although the test system we have chosen for these preliminary studies is the binding of EBNA to the ori-P site of EBV, the screening assay will be applicable to a wide array of medically significant viruses.